Background

In the inflammatory process preceding erosive arthritis, IL-18 plays an important
role. IL-18 is known to regulate immune responses by stimulating Th1 maturation, and
signaling is initiated through formation of a trimeric receptor complex, consisting
out of IL-18 bound to the IL-18Rα and its accessory receptor IL-18Rβ.

Objective

The aim of this study was to determine the physiological role of a recently described
soluble form of the IL-18 receptor accessory protein (sIL-18Rβ) in mice.

Methods

Mouse sIL-18Rβ (genebank accession number AK053176) was cloned from murine lung cDNA
and used for the generation of an adenoviral vector (Ad.5IL-18Rβ). Expression analysis
of the sIL-18Rβ and its full-length membrane bound IL-18Rβ in different murine tissue
was achieved through endpoint PCR. To investigate the in vivo mode of action, sIL-18Rβ was systemically overexpressed in collagen type II-immunized
male DBA/1 mice. Systemical overexpression was achieved through intravenous injection
of 3 × 108 pfu Ad5sIL-18Rβ or the control vector (Ad5Luc) before clinical manifestation of collagen-induced
arthritis (CIA). At 1 and 4 days post adenoviral injection, splenocytes were harvested
and the cytokine profile in plasma and splenocyte culture supernatants was determined

Results

Short IL-18Rβ mRNA was highly expressed in tissue of lymphoid origin, and no expression
could be observed in immune privileged organs like the testis, the eye and the brain,
suggesting a prominent role in immune regulation. Expression of sIL-18Rβ was disease
regulated in mice suffering from CIA, whereas the full-length IL-18Rβ was not regulated.
Splenocytes of sIL-18Rβ-treated immunized mice produced significantly less interferon
gamma and IL-10 compared with control treated animals. Adenoviral overexpression of
the sIL-18Rβ before clinical manifestation of CIA significantly aggravated arthritis,
which was accompanied by a reduction of circulating IL-10, interferon gamma and a
significant increased anti-bovine collagen II IgG1.

Conclusion

Our results describe the existence of a novel short soluble form of the membrane IL-18Rβ,
which is mainly expressed in lymphoid tissues. This sIL-18Rβ expression appears regulated
during CIA. Furthermore, we show that this novel soluble IL-18Rβ functions as a putative
modulator of IL-18 signaling; aggravating CIA, by modulating T-cell immunity.